Food allergy (FA), a condition caused by an immunoglobulin (Ig) E-mediated hypersensitivity reaction to food, is a growing clinical and public health problem in the U.S. Most childhood FA develops in the first few years of life, but there is a lack of a prospective birth cohort study that is specifically designed to identify prenatal precursors of FA in a large U.S. population. While a positive family history is a well-recognized predictor of allergic diseases, specific genetic markers that can modulate individual susceptibility to FA remain largely unexplored. The central focus of this application is to investigate prenatal and genetic factors in relation to the development of FA, using the extensive resources of Boston Birth Cohort. This cohort consists of ~6,000 newborns and their mothers enrolled or being enrolled at the Boston Medical Center. The information collected at the initial recruitment included prenatal epidemiological and clinical variables, birth outcomes, and maternal and cord blood samples. This cohort has been prospectively followed from birth onward to identify incident cases of FA and other allergic diseases. The information collected at postnatal follow-ups includes FA questionnaires;total and food- and aero-allergen-specific IgE;medical records including ICD codes of physician diagnosis;and child's venous blood sample. To maximize cost-efficiency, a nested case-control design will be used, including a total of 400 FA incident cases and 800 non-symptomatic and non-sensitized controls identified from the Boston Birth Cohort. This study's primary aims are: (1) To assess the association of prenatal factors with development of FA in the first two years of life;and (2) To assess the association of candidate gene polymorphisms with development of FA in the first two years of life. This study will focus on promising yet unproven candidate genes involved in the important immune pathways of FA based on current literature, including Antigen presentation;IgE receptor;Innate immunity;TH1 skewing;TH2 skewing;TH17 skewing;T-Regulatory;Inflammatory;Chemokines;and Others. This study has following strengths:(1) highly cost-efficient by using a large, existing birth cohort and a nested case-control design;(2) a prospective data collection that can establish temporal relationships, and provide strong evidence for cause-and-effect;(3) a capability of examining a comprehensive array of prenatal and genetic precursors of FA;(4) a large sample size that assures adequate power to detect causal relations;(5) an innovative gene-environment approach and utilization of the state-of-the-art high-throughput genotyping technology and statistical methods;(6) a highly interactive and experienced research team with a successful track record in conducting molecular and genetic research in this birth cohort and in other populations, and (7) a tremendous potential for future studies of FA, given the well-established infrastructure and resources. This study will help develop a novel and promising paradigm to identify newborns at high risk of developing FA in early childhood, which may lead to interventions that prevent or mitigate FA later in life. Food allergy is emerging as a major clinical and public health problem in the US;and is the most common cause of emergency room visits for anaphylaxis which could be fatal. Most cases of FA developed in the first few years of life;but there is a sparse data on prenatal and genetic influence on the development of FA, which will be the focus of this study.